CN102603646B - Synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole - Google Patents

Synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole Download PDF

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CN102603646B
CN102603646B CN201210079089.6A CN201210079089A CN102603646B CN 102603646 B CN102603646 B CN 102603646B CN 201210079089 A CN201210079089 A CN 201210079089A CN 102603646 B CN102603646 B CN 102603646B
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张玉红
张勋斌
谢永居
黄乐浩
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Zhejiang University ZJU
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Abstract

The invention discloses a novel synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole and belongs to the technical field of organic chemical synthesis. The method comprises the following steps: carrying out reaction on thioanisole and acetyl chloride to generate 4-methylthioacetophenone, carrying out reaction on 4-methylthioacetophenone and methyl benzoate to generate 1-(4-methylthiophenyl)-3-phenyl-1,3-dione, carrying out reaction on 1-(4-methylthiophenyl)-3-phenyl-1,3-dione and tert-butyl nitrite to generate 1-(4-methylthiophenyl)-2-phenyl-1,2-dione, carrying out reaction on 1-(4-methylthiophenyl)-2-phenyl-1,2-dione and trifluoroacetaldehyde methyl hemiacetal to generate 4-[4-(methylthio)phenyl]-5-phenyl-2-(thrifluoromethyl)-1H-imidazole, and finally oxidizing to generate 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole. According to the invention, the synthesis method is adopted, the utilization of cyanide and the damage of KMnO4 to carbon-carbon double bond are avoided, so that the method has industrial application values.

Description

Synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles
Technical field
The present invention relates to organic chemical synthesis technical field, is specifically related to a kind of synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles.
Background technology
Prostaglandin(PG) is being played the part of important role in the production process of inflammation, and the generation that suppresses prostaglandin(PG) is a Basic Ways of anti-inflammatory action.But common NSAID (non-steroidal anti-inflammatory drug), in usually stoping inflammation by inhibition prostate gland, has also suppressed the normal physiological regulation process of prostaglandin(PG).Therefore the use of high dosage antiphlogiston can cause side effect, especially serious ulcer.The action pathway of traditional NSAID (non-steroidal anti-inflammatory drug) is to stop inflammation by suppressing a kind of enzyme cyclooxygenase (COX) relevant with the generation of prostaglandin(PG).
Research shows to replace COX can reach more efficiently the object and the less (Proc.Natl.Acad.Sci of side effect that stop inflammation by suppressing another kind of enzyme cyclooxygenase II (COX II), USA, 89,7384 (1992)).People (the U.s.Pat.No.5 such as Richard M.Weier, 620,999) imidazole derivative is found in research, the structural formula of this imdazole derivatives is suc as formula shown in (1), this imdazole derivatives can high-level efficiency highly selective inhibition COX II, and COX is had to less restraining effect.The wherein IC to COX II 50be less than 0.2 μ M, selectivity is higher than 100.
Figure BDA0000145780070000011
The synthetic method of such glyoxaline compound of report has following several (U.s.Pat.No.5,620,999 at present; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors Bioorganic & Medicinal Chemistry Letters 8 (24): 3443-3448 :)
(1) close ring-oxidising process through condensation-oxidation-condensation.This approach has met early stage needs, but benzoic condensation one step, poor repeatability, is difficult to amplify, and in hydrolytic process, produces hypertoxic HCN, and its reaction process is suc as formula shown in (2).
Figure BDA0000145780070000021
(2) through wittig reaction, two-step oxidation, last condensation is closed ring and is obtained final product.In this reaction scheme, to use KMnO 4, easily causing the fracture of carbon-carbon double bond, its reaction process is suc as formula shown in (3).
Figure BDA0000145780070000022
This reaction path is roughly the same with (2), and difference is that a step both sides substrate is exchanged in wittig reaction, and same, the shortcoming of this route is also KMnO 4easily cause the fracture of carbon-carbon double bond, its reaction process is suc as formula shown in (4).
Figure BDA0000145780070000031
In a word, above-mentioned three kinds of methods have shortcoming separately.A kind of front method is in benzoic condensation one step, and reaction poor repeatability, is difficult to amplify, and in hydrolytic process, produces hypertoxic HCN, limited the method application; Latter two method is being used KMnO 4when oxidation, may cause the fracture of carbon-carbon double bond.
Summary of the invention
The invention provides a kind of synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles; 1; 3 diketone are converted into 1,2 diketone under the effect of cheap iron catalyst, have avoided use and the KMnO of prussiate 4destruction, have industrial applications be worth.
A kind of synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, comprising:
(1) under catalyst action, thioanisole and excess acetyl chloride generate 4-methylthio phenyl ethyl ketone, and described thioanisole and the mol ratio of catalyzer are 1: 1.1~3, are preferably 1.1~2.5, and the mol ratio of thioanisole and Acetyl Chloride 98Min. is 1: 0.5~2;
(2) under catalyst action, described 4-methylthio phenyl ethyl ketone reacts with methyl benzoate and generates 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone, described 4-methylthio phenyl ethyl ketone and catalyst molar ratio are 1: 2~4, and the mol ratio of 4-methylthio phenyl ethyl ketone and methyl benzoate is 1: 0.5~2;
(3) under catalyst action, described 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone and nitrite tert-butyl reaction generate 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone, described 1-(4-methylthio phenyl)-3-phenyl-1, the mol ratio of 3 diketone and catalyzer is 1: 0.1~0.5,1-(4-methylthio phenyl)-3-phenyl-1, and the mol ratio of 3 diketone and nitrite tert-butyl is 1: 3~7;
(4) described 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone react with ammonium acetate and trifluoro acetaldehyde methyl hemiacetal and generate 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, described 1-(4-methylthio phenyl)-3-phenyl-1, the mol ratio of 2 diketone and trifluoro acetaldehyde methyl hemiacetal is 1: 1.1~2,1-(4-methylthio phenyl)-3-phenyl-1, the mol ratio of 3 diketone and ammonium acetate is 1: 1.1~4, is preferably 1.1~3;
(5) described 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles generates described 4-[4-(methylsulfonyl) phenyl after oxygenant oxidation]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, described 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles and oxygenant mol ratio be 1: 1.8~2.2.
Catalyzer described in step (1) is aluminum chloride, iron trichloride or zinc dichloride, and reaction is carried out in the organic solvents such as methylene dichloride, trichloromethane or dithiocarbonic anhydride; When temperature of reaction is too low, reaction not exclusively, when temperature of reaction is too high, has impurity to produce in product, all affects the productive rate of product, and therefore, preferred as one, the temperature of reaction in step (1) is 10~30 ℃; Reaction times is not very large on the impact of productive rate, generally will the reaction times be controlled at 10-20 hour, is all that reaction is spent the night in general situation, in 10-20 hour, all can.
Catalyzer described in step (2) is sodium hydride, sodium tert-butoxide, potassium tert.-butoxide or trimethyl carbinol lithium, is preferably hydrogenation and receives, and reaction is carried out in tetrahydrofuran (THF) or DMF; When temperature of reaction is too low, reaction not exclusively, when temperature of reaction is too high, has impurity to produce in product, all affects the productive rate of product, and therefore, preferred as one, the temperature of reaction in step (2) is 50~70 ℃; Reaction times is 10-20 hour, is all that reaction is spent the night in general situation, in 10-20 hour, all can.
Catalyzer described in step (3) is iron trichloride, ferric bromide, iron protochloride or ferric oxide; When temperature of reaction is too low, reaction not exclusively, when temperature of reaction is too high, has impurity to produce in product, all affects the productive rate of product, and therefore, preferred as one, the temperature of reaction in step (3) is 20-40 ℃; Reaction times is 10-20 hour, is all that reaction is spent the night in general situation, in 10-20 hour, all can.
Reaction described in step (4) is carried out in acetic acid; When temperature of reaction is too low, reaction not exclusively, when temperature of reaction is too high, has impurity to produce in product, all affects the productive rate of product, and therefore, preferred as one, the temperature of reaction in step (4) is 90-110 ℃; Reaction times is 10-20 hour.
The reaction of step (5) is carried out in methylene dichloride or trichloromethane, described oxygenant is metachloroperbenzoic acid, hydrogen peroxide, peracetic acid or potassium permanganate, be preferably hydrogen peroxide, while oxidation, can not relate to carbon-carbon double bond herein, so can adopt potassium permanganate, oxidation is carried out under condition of ice bath, and oxidization time is 30-60min.
The detailed process of above step (1)~(5) is as follows:
(1) make solvent with methylene dichloride (DCM), trichloromethane or dithiocarbonic anhydride etc., in the time of 0~20 ℃, add thioanisole and catalyzer, under agitation condition, drip Acetyl Chloride 98Min., after dropwising, be warming up to room temperature (10~30 ℃), stir 10-20 hour; After completion of the reaction, add trash ice to reaction solution, drip concentrated hydrochloric acid to pH1~3, under room temperature, stir 15min, with dichloromethane extraction, organic phase washes with water successively, saturated common salt washing, except the mixed solvent recrystallization of sherwood oil and ethyl acetate for desolventizing gained crude product, obtain intermediate 4-methylthio phenyl ethyl ketone;
(2) make solvent with tetrahydrofuran (THF) or DMF, add catalyzer, stir after 10 minutes, add methyl benzoate, drip 4-methylthio phenyl ethyl ketone, after dropwising, be warming up to 50~70 ℃, stir 10-20 hour.After completion of the reaction, drip water, then add rare HCl to be adjusted to pH2~4, CH 2cl 2extraction, anhydrous sodium sulfate drying, except desolventizing gained crude product silicagel column purifying (sherwood oil: ethyl acetate=50: 1), obtain intermediate 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone;
(3) to catalyzer and 1-(4-methylthio phenyl)-3-phenyl-1, in the mixture of 3 diketone, add nitrite tert-butyl (TBN), at 20-40 ℃, stir 10-20 hour, after completion of the reaction, filter, except desolventizing gained crude product silicagel column purifying (sherwood oil: ethyl acetate=40: 1), obtain intermediate 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone, wherein nitrite tert-butyl can be easy to prepare by the trimethyl carbinol and Sodium Nitrite industrial;
(4) take acetic acid as solvent, add 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone, trifluoro acetaldehyde methyl hemiacetal and ammonium acetate, in 90-110 ℃ of reaction 10-20 hour, after completion of the reaction, add saturated Na 2cO 3solution regulates pH8~10, be extracted with ethyl acetate again, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, except desolventizing gained crude product with silicagel column purify (sherwood oil: ethyl acetate=5: 1), obtain intermediate 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles;
(5) take methylene dichloride as solvent, add 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, at 0 ℃, drip wherein oxygenant as the dichloromethane solution of metachloroperbenzoic acid (mCPBA), after dropwising, continue to stir 30-60min under condition of ice bath, add the saturated solution of Sulfothiorine, with dichloromethane extraction, anhydrous sodium sulfate drying, on Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtaining white solid is end product 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles.
The reaction process of synthetic method of the present invention represents suc as formula shown in (5) with chemical equation, wherein in step (1) catalyzer used take aluminum chloride as example, catalyzer used in step (2) is received as example with hydrogenation, catalyzer used in step (3) is take iron trichloride as example, and oxygenant used in step (5) is take metachloroperbenzoic acid as example:
Figure BDA0000145780070000061
Beneficial effect of the present invention:
(1) yield is high, and cost is low, uses cheap raw material and catalyzer;
(2) avoided the generation of hypertoxic prussiate, more friendly to environment;
(3) prepare 1,2-diketone by 1,3-diketone, avoided strong oxidizer KMnO 4to the destruction of carbon-carbon double bond, by product is few.
Embodiment
Productive rate in all embodiment is all take the few substrate of molar weight as benchmark below
Embodiment 1
Synthesizing of step 1 4-methylthio phenyl ethyl ketone
Figure BDA0000145780070000071
In 250mL round-bottomed flask, add thioanisole (25g, 200mmol) and methylene dichloride (150mL); Under 0 ℃ of agitation condition, add wherein aluminum chloride (40g, 300mmol), then slowly drip Acetyl Chloride 98Min. (16g, 15mL, 200mmol); After dropwising, naturally rise to room temperature, stir 12 hours.After TLC (thin-layer chromatography) shows that reaction finishes, by reaction solution impouring trash ice, then add concentrated hydrochloric acid to adjust pH to 2 left and right.Under room temperature, stir 15min, use dichloromethane extraction three times, merge organic phase.Organic phase washes with water successively, saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, the mixed solvent recrystallization of sherwood oil and ethyl acetate for gained crude product, obtains white solid 4-methylthio phenyl ethyl ketone 20g, productive rate 60%.
1H?NMR(400MHz,CDCl 3,TMS):δ7.87(d,2H,J=8.8Hz),7.27(d,2H,J=8.8Hz),2.57(s,3H),2.52(s,3H); 13C?NMR(125MHz,CDCl 3,TMS)197.0,145.8,133.4,128.6,124.8,26.3,14.6.
Step 2 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone synthetic
Figure BDA0000145780070000072
In 250mL single port flask, add sodium hydride (60%1.8g 45mmol) and dry tetrahydrofuran (THF) (30mL); Under ice bath, stir after 10min, add methyl benzoate (2.7g 19.8mmol), and then drip 4-methylthio phenyl ethyl ketone (3g 18mmol); After dropwising, be warming up to 60 ℃, stir 12 hours.After TLC shows and reacts completely, to dripping the shrend reaction of going out in this reaction system, then add dilute hydrochloric acid to be adjusted to about pH3, dichloromethane extraction three times, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent gained crude product silicagel column purifying (sherwood oil: ethyl acetate=50: 1), obtain yellow solid 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 3.1g, productive rate 63%.
1H?NMR(400MHz,CDCl 3,TMS):δ16.93(s,1H),7.97-7.99(m,2H),7.91(d,2H,J=8.4Hz),7.55(t,1H,J=7.6Hz),7.49(t,2H,J=7.6Hz),7.30(d,2H,J=8.0Hz),6.82(s,1H),2.54(s,3H); 13C?NMR(125MHz,CDCl 3,TMS):δ185.4,184.9,145.1,135.4,132.3,131.6,128.6,127.4,127.0,125.2,92.6,14.8.
Step 3 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone synthetic
In test tube, add iron trichloride (128mg, 0.8mmol), 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone (1.1g, 4mmol) and nitrite tert-butyl (2g, 19mmol), stir 12 hours in 30 ℃.After TLC demonstration reacts completely, diatomite filtration, is spin-dried for solvent, gained crude product silicagel column purifying (sherwood oil: ethyl acetate=40: 1), obtain yellow solid 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone 768mg, productive rate 74%.
1H?NMR(400MHz,CDCl 3,TMS):δ7.96(dd,2H,J=8.4,1.2Hz),7.87(d,2H,J=8.4Hz),7.65(t,1H,J=7.6Hz),7.50(t,2H,J=7.6Hz),7.28-7.30(m,2H),2.52(s,3H); 13C?NMR(125MHz,CDCl 3,TMS):194.5,193.4,148.9,134.7,133.0,130.0,129.8,129.1,128.9,125.0,14.5.
Step 4 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
Figure BDA0000145780070000082
In 25mL round-bottomed flask, add 1-(4-methylthio phenyl)-3-phenyl-1,2 diketone (512mg, 2mmol), trifluoro acetaldehyde methyl hemiacetal (572mg, 4mmol), ammonium acetate (462mg, 6mmol) and acetic acid (5mL), 110 ℃ are refluxed 12 hours.After TLC demonstration reacts completely, add saturated Na 2cO 3solution is adjusted to pH9 left and right, and ethyl acetate extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying (PE: EA=5: 1), obtain white solid 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 370mg, productive rate 55%.
1H?NMR(400MHz,DMSO-d6,TMS):δ13.84(br,1H),7.23-7.55(m,9H),2.56(s,3H);MS(EI,M/e):334。
Step 5 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
Figure BDA0000145780070000091
At 0 ℃, to 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles (167mg, in methylene dichloride (10mL) solution 0.5mmol), drip metachloroperbenzoic acid (75%, 241mg, 1.05mmol) methylene dichloride (10mL) solution; After dropwising, continue to stir 30min under condition of ice bath, add the saturated solution of Sulfothiorine; With dichloromethane extraction three times, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtains white solid 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 158mg, productive rate 86%.
1H?NMR(400MHz,DMSO-d6,TMS):δ14.00(br,1H),7.49-7.73(m,9H),2.76(s,3H),MS(ESI,(M-H) -):364.9.。
Embodiment 2
Synthesizing of step 1 4-methylthio phenyl ethyl ketone
In 250mL round-bottomed flask, add thioanisole (25g, 200mmol) and methylene dichloride (150mL); Under 0 ℃ of agitation condition, add wherein iron trichloride (80g, 500mmol), then slowly drip Acetyl Chloride 98Min. (32g, 30mL, 400mmol); After dropwising, naturally rise to room temperature, stir 12 hours.After TLC shows that reaction finishes, by reaction solution impouring trash ice, then add concentrated hydrochloric acid to adjust pH2 left and right.Under room temperature, stir 15min, use dichloromethane extraction three times, merge organic phase.Organic phase washes with water successively, saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, the mixed solvent recrystallization of sherwood oil and ethyl acetate for gained crude product, obtains white solid 4-methylthio phenyl ethyl ketone 14g, productive rate 42%.
Step 2 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone synthetic
In 250mL single port flask, add sodium hydride (60%, 1.4g, 36mmol) and dry tetrahydrofuran (THF) (30mL).Under ice bath, stir after 10min, add methyl benzoate (1.2g, 9mmol), and then drip 4-methylthio phenyl ethyl ketone (3g, 18mmol); After dropwising, be warming up to 60 ℃, stir 12 hours.After TLC shows and reacts completely, to dripping the shrend reaction of going out in this reaction system, then add dilute hydrochloric acid to be adjusted to about pH3, dichloromethane extraction three times, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying (sherwood oil: ethyl acetate=50: 1), obtain yellow solid 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 1.8g, productive rate 74% (the substrate methyl benzoate few with respect to molar weight).
Step 3 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone synthetic
In test tube, add iron protochloride (51mg, 0.4mmol), 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone (1.1g, 4mmol) and nitrite tert-butyl (1.2g, 12mol), stir 12 hours in 30 ℃.After TLC demonstration reacts completely, diatomite filtration, is spin-dried for solvent, gained crude product silicagel column purifying (sherwood oil: ethyl acetate=40: 1), obtain yellow solid 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone 531mg, productive rate 51%.
Step 4 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
In 25mL round-bottomed flask, add 1-(4-methylthio phenyl)-3-phenyl-1,2 diketone (512mg, 2mmol), trifluoro acetaldehyde methyl hemiacetal (314mg, 2.2mmol), ammonium acetate (127mg, 2.2mmol) and acetic acid (5mL), 110 ℃ are refluxed 12 hours.After TLC demonstration reacts completely, add saturated Na 2cO 3solution is adjusted to pH9 left and right, and ethyl acetate extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying (PE: EA=5: 1), obtain white solid 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 290mg, productive rate 43%.
Step 5 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
At 0 ℃, to 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles (167mg, in methylene dichloride (10mL) solution 0.5mmol), drip hydrogen peroxide (30%, 102mg, 0.9mmol) methylene dichloride (10mL) solution.After dropwising, continue to stir 30min under condition of ice bath, add the saturated solution of Sulfothiorine.With dichloromethane extraction three times, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtains white solid 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 124mg, productive rate 68%.
Embodiment 3
Synthesizing of step 1 4-methylthio phenyl ethyl ketone
In 250mL round-bottomed flask, add thioanisole (25g, 200mmol) and trichloromethane (150mL); Under 0 ℃ of agitation condition, add wherein aluminum chloride (32g, 240mmol), then slowly drip Acetyl Chloride 98Min. (8g, 7.5mL, 100mmol); After dropwising, naturally rise to room temperature, stir 12 hours.After TLC shows that reaction finishes, by reaction solution impouring trash ice, then add concentrated hydrochloric acid to adjust pH2 left and right.Under room temperature, stir 15min, use dichloromethane extraction three times, merge organic phase.Organic phase washes with water successively, saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, the mixed solvent recrystallization of sherwood oil and ethyl acetate for gained crude product, obtains white solid 4-methylthio phenyl ethyl ketone 17g, productive rate 51%.
Step 2 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone synthetic
In 250mL single port flask, add sodium hydride (60%, 2.9g, 72mmol) and dry tetrahydrofuran (THF) (30mL); Under ice bath, stir after 10min, add methyl benzoate (4.9g, 36mmol), and then drip 4-methylthio phenyl ethyl ketone (3g, 18mmol); After dropwising, be warming up to 60 ℃, stir 12 hours.After TLC shows and reacts completely, to dripping the shrend reaction of going out in this reaction system, then add dilute hydrochloric acid to be adjusted to about pH3, dichloromethane extraction three times, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent gained crude product silicagel column purifying (sherwood oil: ethyl acetate=50: 1), obtain yellow solid 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 3.1g, productive rate 63%.
Step 3 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone synthetic
In test tube, add ferric oxide (319mg, 2mmol), 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone (1.1g, 4mmol) and nitrite tert-butyl (2.9g, 28mmol), stir 12 hours in 30 ℃.After TLC demonstration reacts completely, diatomite filtration, is spin-dried for solvent, gained crude product silicagel column purifying (sherwood oil: ethyl acetate=40: 1), obtain yellow solid 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone 596mg, productive rate 57%.
Step 4 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
In 25mL round-bottomed flask, add 1-(4-methylthio phenyl)-3-phenyl-1,2 diketone (512mg, 2mmol), trifluoro acetaldehyde methyl hemiacetal (429mg, 3mmol), ammonium acetate (385mg, 5mmol) and acetic acid (5mL), 110 ℃ are refluxed 12 hours.After TLC demonstration reacts completely, add saturated Na 2cO 3solution is adjusted to pH9 left and right, and ethyl acetate extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying (PE: EA=5: 1), obtain white solid 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 335mg, productive rate 50%.
Step 5 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles synthetic
At 0 ℃, to 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles (167mg, in methylene dichloride (10mL) solution 0.5mmol), drip methylene dichloride (10mL) solution of potassium permanganate (172mg, 1.1mmol).After dropwising, continue to stir 30min under condition of ice bath, add the saturated solution of Sulfothiorine.With dichloromethane extraction three times, anhydrous sodium sulfate drying.On Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtains white solid 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 115mg, productive rate 63%.
Product in embodiment 2 and embodiment 3 in every step reactions steps all contrasts by TLC, is defined as consistent with every step reactions steps products therefrom corresponding in embodiment 1.

Claims (1)

1. synthetic 4-[4-(methylsulfonyl) phenyl] method of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles, it is characterized in that, step is as follows:
(1) in 250mL round-bottomed flask, add thioanisole 25g and methylene dichloride 150mL; Under 0 ℃ of agitation condition, add wherein aluminum chloride 40g, then slowly drip Acetyl Chloride 98Min. 16g; After dropwising, naturally rise to room temperature, stir 12 hours, after TLC shows that reaction finishes, by reaction solution impouring trash ice, then add concentrated hydrochloric acid to adjust pH to 2 left and right, under room temperature, stir 15min, use dichloromethane extraction three times, merge organic phase; Organic phase washes with water successively, saturated common salt washing, and anhydrous sodium sulfate drying revolves except organic solvent on Rotary Evaporators, and the mixed solvent recrystallization of sherwood oil and ethyl acetate for gained crude product, obtains white solid 4-methylthio phenyl ethyl ketone 20g, productive rate 60%;
(2) to adding 60% sodium hydride 1.8g and dry tetrahydrofuran (THF) 30mL in 250mL single port flask; Under ice bath, stir after 10min, add methyl benzoate 2.7g, and then drip 4-methylthio phenyl ethyl ketone 3g; After dropwising, be warming up to 60 ℃, stir 12 hours; After TLC shows and reacts completely, to dripping the shrend reaction of going out in this reaction system, then add dilute hydrochloric acid to be adjusted to about pH3, dichloromethane extraction three times, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product is purified with silicagel column, the sherwood oil that leacheate is 50:1: the mixed solvent of ethyl acetate, obtains yellow solid 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 3.1g, productive rate 63%;
(3) in test tube, add iron trichloride 128mg, 1-(4-methylthio phenyl)-3-phenyl-1,3 diketone 1.1g and nitrite tert-butyl 2g, stir 12 hours in 30 ℃; After TLC demonstration reacts completely, diatomite filtration, is spin-dried for solvent, gained crude product silicagel column purifying, the sherwood oil that leacheate is 40:1: the mixed solvent of ethyl acetate, obtains yellow solid 1-(4-methylthio phenyl)-2-phenyl-1,2 diketone 768mg, productive rate 74%;
(4) in 25mL round-bottomed flask, add 1-(4-methylthio phenyl)-3-phenyl-1,2 diketone 512mg, trifluoro acetaldehyde methyl hemiacetal 572mg, ammonium acetate 462mg and acetic acid 5mL, 110 ℃ are refluxed 12 hours; After TLC demonstration reacts completely, add saturated Na 2cO 3solution is adjusted to pH9 left and right, and ethyl acetate extraction, merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product silicagel column purifying, leacheate is the sherwood oil of 5:1: the mixed solvent of ethyl acetate, obtains white solid 4-[4-(methylthio group) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 370mg, productive rate 55%;
(5) at 0 ℃, to 4-[4-(methylthio group) phenyl] drip the 10mL dichloromethane solution of 75% metachloroperbenzoic acid 241mg in the 10mL dichloromethane solution of-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 167mg; After dropwising, continue to stir 30min under condition of ice bath, add the saturated solution of Sulfothiorine; With dichloromethane extraction three times, anhydrous sodium sulfate drying; On Rotary Evaporators, revolve except organic solvent, gained crude product MeOH recrystallization, obtains white solid 4-[4-(methylsulfonyl) phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazoles 158mg, productive rate 86%.
CN201210079089.6A 2012-03-22 2012-03-22 Synthesis method of 4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole Expired - Fee Related CN102603646B (en)

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